Cyclopentanophenanthrene derivatives and process



United States Patent Office 3,410,907 Patented Nov. 12, 1968 3,410,907CYCLOPENTANOPHENANTHRENE DERIVATIVES AND PROCESS John A. Edwards, PaloAlto, Calif., assignor to Syntex Corporation, Panama, Panama, acorporation of Panama No Drawing. Filed Aug. 4, 1965, Ser. No. 477,31920 Claims. (Cl. 260-586) ABSTRACT OF THE DISCLOSURE Novel Bhomo-19-nor-A and A -androsten-3p-ol steriods which are, inter alia,anabolic and progestational agents and processes for the preparation ofsuch compounds.

This invention relates to novel cyclopentanopolyhydrophenanthrenederivatives and to processes for the preparation thereof.

More particularly, this invention relates to novel B- homo-19nor-A and A-androsten-3B-ols and 3-esters and ethers thereof represented by thegeneral formula:

In the above formula, R represents a hydroxy group, an acyloxy group, atetrahydrofuranyloxy group or a tetrahydropyranyloxy group, R representshydrogen, a lower alkyl (including cycloalkyl) group, such as methyl,ethyl, propyl, cyclopropyl, butyl, cyclobutyl, and the like, a loweralkenyl group, such as vinyl and the like, or a lower alkynyl (includinghalo-lower alkynyl) group, such as ethynyl, fluoroethynyl,chloroethynyl, bromoethynyl, propynyl, trifluoropropynyl, butynyl,hexynyl, and the like; R and R taken together may represent a ketogroup; R represents hydrogen, an acyl group, a tetrahydrofuranyl groupor a tetrahydropyranyl group, and the dotted lines indicate that thereis one double bond at either the 4(5)- or the 5(10)-position.

The acyl and acyloxy groups referred to herein are preferably derivedfrom hydrocarbon carboxylic acids containing less than 12 carbon atomswhich may be saturated or unsaturated, of straight, branched, cyclic orcyclic-aliphatic chain, aromatic and may be substituted by functionalgroups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino or halogen. Typical estergroups are the acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyaceate, cyclopentylpropionate,aminoacetate, and ,B-chloropropionate.

The novel B-homo steriods represents by the above formula wherein R isother than alkynyl are anabolic agents with a favorableanabolic-androgenic ratio. They also have antiestrogenic,antigonadotrophic and antifibrillatory properties, lower bloodcholesterol levels, and suppress the output of the pituitary gland.

The novel B-homo steroids described above wherein R represents a loweralkynyl group are progestational agents having antiandrogenic,antiestrogenic, antigonadotrophic and diuretic properties. In addition,they can be used in fertility control, in the treatment of premenstrualtension, and in lowering blood cholesterol levels.

The novel B homo-19-nor-A -androsten-Bli-ols, 3-

others and esters thereof of the present invention may be prepared by aprocess illustrated in the following equation:

OH O

I II

R 0 R30 .s l W III 0 o I I -.D R30 R20 VII In the above formulas R and Rhave the same meanings as previously described and R represents an acylgroup.

In practicing the process outlined above, the starting material I, aB-homo-19-nor-A -androstene-3p,7(a or 18)-diol-17-one 3-acylate, suchas, B-homo-19-nor-A andnostene-3,8,7fl-diol-l7-one 3-acetate (I; R=acetyl, ob tained as described in my copending US. patent applicationSer, No. 423,566, filed J an. 5, 1965, now abandoned, is ketalized in aknown manner with. a lower alkylene glycol, such as ethylene glycol,propylene glycol, or the like, to give the corresponding 17-ketal, thatis, B-homo- 17 cycloethylened-ioxy 19-nor-A androstene-3fl,7fldiolS-acetate. The 7-hydroxy group of the resulting 17- ketal is thenoxidized, using chromium trioxide in pyridine, or the like, preferablyat room temperature overnight, to give the corresponding 7-keto steroid,B-homo- 17 cycloethylenedioxy-19-nor-A -androstene-3[i-ol-7- one3-acetate (II; R =acetyl).

The latter compound is then reacted with a lower alkylene dithiol, suchas ethanediol, propanedithiol, or the like, to give the corresponding7-cycloalkylene dithioketal, that is,B-homo-l7-cycloethylenedioxy-7-cycloethylenedithio-l9-nor-A-androsten-3fl-ol 3-acetate (Ill; R =acetyl). The latter derivative isthen selectively hydrogenolyzed as by refluxing with Raney nickel in asolvent such as a lower alkanol from about 8 to about 24 hours, to formthe corresponding 7-desoxy steroid, B- homo17-cycloethylenedioxy-l9-nor-A -androsten-3B- ol 3-acetate (IV; R=acetyl).

Removal of the protective cyclic ketal moiety from the foregoingcompound as by refluxing in an inert organic solvent, preferably aketone such as acetone, methylethyl ketone, methyl isobutyl ketone, orthe like, with a strong acid, such as sulfuric acid, hydrochloric acid,ptoluenesulfonic acid, or the like, affords the corresponding l7-ketosteroid, B-homo-19-nor-A -androsten-3flol-17-one 3-acetate (V; R=acetyl).

Conventional saponification of the latter compound furnishes thecorresponding free alcohol (VI; R hydrogen).

The 3,8-hydroxy compound may be reesterified by conventional means toform esters other than the acetate by treatment with a differentacylating agent derived from a hydrocarbon carboxylic acid of less than12 carbon atoms of the type described previously.

Reaction of the free 3fi-hydroxy compound with dihydrofuran ordihydropyran in benzene, under substantially anhydrous conditions, inthe presence of a small amount of an acid catalyst, such as,p-toluenesulfonic acid, boron trifluoride etherate, or the like,preferably from about room temperature to about 50 C., from about 1 toabout 72 hours, gives the corresponding 3- tetrahydrofuranyl ortetrahydropyranyl ether.

By reacting the free 3Bol-l7-one or a 3-ester or ether thereof,dissolved in an aqueous ether solution, such as, an aqueous dioxane ortetrahydrofuran solution containing from about to about 20% water, orthe like, with a double metal hydride, such as lithium aluminum hydride,sodium borohydride, and the like, preferably the latter, at atemperature ranging from room temperature to reflux temperature forabout 1 hour to about 24 hours, the corresponding 3,8,17fl-diol or3-ester or ether thereof, that is, B-homo-l9-nor-A -androstene-3B,17B-diol (VII; R and R =hydrogen), is obtained.

Reaction of the free 3,8-ol-l7-one or a 3-ester or ether thereof,dissolved in an inert organic solvent, preferably thiophene-freebenezene, at reflux temperature under substantially anhydrous conditionsfor about 3 hours or longer, with a lower alkyl, alkenyl or alkynylmagnesium halide, such as methyl, vinyl or ethynyl magnesium bromide, orthe like, produces the corresponding l7a-lower alkyl, -lower alkenyl orlower alkynyl-17/3-hydroxy derivative (VII; R =lower alkyl, alkenyl oralkynyl, R hydrogen).

Where necessary, these lt-SubStltlltCd and -unsubstituted 1713-015 canthen be reesterified or reetherified at the 3-position, or esterified oretherified at the l-position, using conventional techniques, i.e., thosementioned hereinabove in the case of 3-esters and 3- or l7-ethers and3,17-bis-ethers, or by reaction at room temperature with a mixture ofthe appropriate acid anhydride and the corresponding acid, in thepresence of a catalytic amount of p-toluenesulfonic acid and undersubstantially anhydrous conditions, in the case of 17-esters and3,17-diesters.

Similarly, a lower alkyl, alkenyl or alkynyl lithium compound, such asethyl lithium, vinyl lithium, ethynyl lithium, or the like, in absolutediethyl ether and under an inert nitrogen atmosphere, can be used toconvert the free 3fl-ol-l7-one, by reaction at room temperature for 48hours or longer, to the corresponding 17a-lower alkyl, -lower alkenyl or-lower alkynyl-l7B-hydroxy derivative.

The 17-one, dissolved in anhydrous benzene containing potassiumt-amylate, can also be reacted with gaseous acetylene under an inertnitrogen atmosphere for 36 hours wherein X represents chloro or bromoand Y represents fluoro, chloro, bromo or fluoro-lower alkyl, e.g.,trifluoromethyl, such as l-chloro-Z-fluoroethylene;1,2-dichloroethylene; 1,2-dibromoethylene;1-chloro-3,3,3trifluoropropyl-l-ene;l-bromo-3,3,3-trifluoropropyl-l-ene, or the like, in anhydrousdiethylether under an inert nitrogen atmosphere at 0 C., with a solutionof methyl lithium in anhydrous diethyl ether (prepared, for example, byadding lithium to methyl iodide in anhydrous diethyl ether solutionunder an inert nitrogen atmosphere at about 10 C.). This mixture is thenheld at room temperature, with stirring, for from about minutes to about2 hours, following which the 3fl-ol-l7-one dissolved in anhydrousdiethyl ether, is slowly added and the resulting reaction mixture isheld at room temperature for from about 12 hours to about 18 hours togive the corresponding chaloalkynyl derivative. Where1-chloro-2-fluoroethylene; 1,2-dichloroethylene, 1,2-dibromoethylene andl-chloro- 3,3,3-trifluoropropyl-1-ene, respectively, are used, a17ccfluoroethynyl, 17x-chloroethynyl, 17a-bromoethynyl and17a-trifluoropropynyl substituent, respectively, is obtained.

The novel B-homo-l9-nor-A -androsten 3fl-ols, 3-esters and -ethersthereof hereinabove described are prepared by a process illustrated bythe following equation A a. grffi O o H l H I o- J R40 J 0 on I no l pl/R 0 h- R o' J xrv XIII CO i) In the above formulas R R and R have thesame meanings as set forth hereinabove and R represents hydrogen oracyl. I

In carrying out the above process, the starting material V, aB-homo-l9-nor-A -androsten-3fl-ol-l7-one 3-acylate, for exampleB-homo-19 nor-A -androsten-3/3-ol-17- one 3-acetate (V; R =acetyl),dissolved in an aqueous ether solution, is reacted with a double metalhydride in the manner described hereinabove to provide the corresponding175-01, e.g., B-homo-19-nor-A -androstene- 35,175-diol 3-acetate, (VIII;R =acetyl).

The free l7fi-hydroxy group in this 175-01 is then etherified withdihydropyran, in the manner described hereinabove, to give thecorresponding 17B-tetrahydropyranyloxy derivative, e.g.,B-homo-19-nor-Eli-tetrahydropyranyloxy-A -androsten-3fl-ol 3-acetate(IX; R =acetyl) which upon hydrolysis in the manner describedhereinabove, affords the corresponding free 3,8-hydroxy steroid,B-homo-l9-nor 17,8 tetrahydropyranyloxy-A -androsten-3fi-ol (IX; R=hydrogen). Oxidation of the thusobtained B/B-hydroxy steroid withchromium trioxide in pyridine, preferably at room temperature overnight,gives B homo l9-nor-17,8-tetrahydropyranyloxy-A -androsten-3one (X)which upon refluxing with an aqueous methanolic solution of sodiumhydroxide, potassium hydroxide, or the like, preferably of from about0.01 N to about 0.1 N, under an inert nitrogen atmosphere for from aboutone to about six hours, to give the corresponding 19-norA -3-one,B-homo-19-nor-17,8-tetrahydropyranyloxy-. A -androsten-3-one (XI).

Upon refluxing the thus-obtained l9-nor-A -3-one with lithium aluminumhydride in tetrahydrofuran, under substantially anhydrous conditions,there is obtained the corresponding l9-nor-A -3fi-ol,B-homo-l9-nor-17fl-tetra hydropyranyloxy A androsten-3 [3-01 (XII; R=hydrogen), which, upon esterification in the manner describedhereinabove, affords the corresponding 3-acylate, B-homo- 19 nor17,8-tetrahydropyranyloxy-M-androsten-Zifi-ol 3- acylate (XII; R =acyl).

The thus-obtained 3-acylate, dissolved in aqueous lower alkanol, such asmethanol, ethanol, or the like, is then reacted with oxalic acid at atemperature ranging from about room temperature to reflux temperaturefor about 10 minutes to about 2 hours or longer to remove thetetrahydropyranyl group, thus giving the corresponding free 17,6-hydroxy3-acylate, e.g., Ei-homo-l9-nor-A -androstene-3fi,l7/3-diol 3-acylate(XIII; R =acyl). Upon oxidation of the latter compound with chromiumtrioxide in pyridine in the manner described hereinabove, there isobtained the corresponding 17-one, e.g., B-homo-19-nor- A-androsten-3fi-old7-one 3-acylate (XVI; R =acyl).

The introduction of 170L-SllbStltll6I1tS, 3- and 17-ester and ethergroups, and the like, to give the various compounds encompassed byFormulas XIV and XV, can be accomplished in the manner describedhereinabove for the corresponding 19-nor-A -compounds of Formulas VI andVII.

In order that those skilled in the art can more fully understand thepresent invention, the following examples are set forth. These examplesare given solely for the purpose of illustrating the invention, andshould not be considered as expressing limitations unless so set forthin the appended claims.

EXAMPLE I A mixture of 1 gram of B-homo-l9-nor-A-androstene-3fi,7/3-diol-17-one 3-acetate 1; R =acetyl), 25 cc. ofanhydrous, thiophenc-free benzene, 5 cc. of ethylene glycol and 50 mg.of p-toluenesulfonic acid monohydrate was refluxed for 16 hours withdistillation of the water formed during the reaction. Following thisreaction period the reaction mixture was washed with an aqueous sodiumbicarbonate solution, then with water, then dried over anhydrous sodiumsulfate, and finally evaporated to dryness. Recrystallization fromacetone/hexane gave B- homo-l7-cycloethylenedioxy-19-nor-A -androstene35, 7/3-diol 3-acetate.

EXAMPLE II A solution of 6 grams ofB-homo-17-cycloethylenedioxy-l9-nor-A -androstene-3fiJB-diol 3-acetatein 120 cc. of pyridine was added to a mixture of 6 grams of chromiumtrioxide in 120 cc. of pyridine, and the resulting reaction mixture wasthen allowed to stand at room temperature (25 C.) overnight. Followingthis reaction period the reaction mixture was diluted with ethyl acetateand then filtered through Celite. The resulting filtrate was Washedthoroughly with water, then dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization from acetone/ hexane gaveB-homo-17-cycloethylenedioxy- 19-nor-A -androsten-3fl-ol-7-one3-acetate.

EXAMPLE III A solution of 5 grams ofB-homo-17-cycloethylenedioxy-19-nor-A -androsten-3p-ol-7-one 3-acetatein cc. of glacial acetic acid containing 5 cc. of ethanedithiol wasadmixed with 4 cc. of a saturated solution of hydrogen chloride inacetic acid, and the resulting reaction mixture was then allowed tostand at room temperature for 4 hours. Following this reaction periodthe reaction mixture was admixed with water and then saturated withethyl acetate. The resulting extract was washed with an aqueous 5%sodium bicarbonate solution, then with water, then dried over anhydroussodium sulfate and finally evaporated to dryness. Recrystallization fromdiethyl ether/hexane gaveB-homo-7-cycloethylenedithio-17-cycloethylenedioxy-l9-nor A500)androsten-Sfi-ol 3-acetate.

EXAMPLE IV A solution of 4 grams ofB-horno-7-cycloethylenedithio-17-cycloethylenedioxy-19-nor-A -androsten35- ol 3-acetate in 3 liters of ethanol (previously distilled from Raneynickel), containing 50 grams of Raney nickel, was refluxed for 6 hours.Following this reaction period the reaction mixture was filtered toremove the Raney nickel, which was then washed with hot ethanol and thewashings added to the filtrate. The combined ethanol solution was thenevaporated to dryness, and the resulting residue was dissolved inchloroform. This chloroform solution was washed with dilute hydrochloricacid, then with aqueous sodium carbonate solution and finally withwater. The solution was then dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the thus-obtained residue fromacetone/hexane gave B- homo-17-cycloethylenedioxy-l9-nor A500)androsten- 3,6-01 3-acetate.

EXAMPLE V A solution of 2 grams of B-homo-l7-cyclotheylenedioxyl9-nor-A-androsten-Bfl-ol 3-acetate in 70 cc. of methanol containing 7 ml. ofaqueous 8% sulfuric acid was refluxed for 10 minutes. Following thisreaction period the reaction mixture was neutralized by the addition ofaqueous sodium carbonate solution, then concentrated to a volume ofabout ml. under vacuum and poured into water. The thus-formedprecipitate was then collected by filtration and washed thoroughly withwater. Recrystallization from acetone gave B-homo-19-nor- A-androsten-3B-ol-17-one 3-acetate.

EXAMPLE VI A solution of 1 gram of B-homo-19-nor-A-androsten-3B-ol-17one 3-acetate in 50 cc. of methanol was refiuxed for3 hours with 500 mg. of potassium hydroxide dissolved in 1 cc. of water.Following this reaction period the reaction mixture was poured into icewater and the resulting precipitate collected by filtration, washed withwater until neutral and then dried. Recrystallization from methylenedichloride/diethyl ether gave B-homo- 19-nor-A -androsten-3,8-ol-17-one.

EXAMPLE VII A solution of 1 gram of sodium borohydride in 15 cc. ofwater was added to a solution of 1 gram of B- homo-19-nor-A-androsten-SB-ol-17-one in 120 cc. of tetrahydrofuran, and the resultingreaction mixture was then refluxed for 2 hours. Following this reactionperiod the reaction mixture was cooled to room temperature, treated withacetic acid to decompose excess borohydride, and then concentrated to asmall volume under vacuum and diluted with water. The dilute solutionwas then extracted with ethyl acetate, and the resulting extract waswashed with water, dried over anhydrous sodium sulfate and evaporated todryness. Crystallization of the resulting residue from acetone/hexanegave B-homo-l9-nor- A -andr0stene-3fl,17{5-diol.

EXAMPLE VIII A solution of 5 grams of B-homo-19-nor-A-androsten-3B-ol-17-one in -0 cc. of thiophene-free benzene was admixedwith 27.5 cc. of a 4 N solution of methylmagnesium bromide in diethylether, and the resulting reaction mixture was refluxed, excludingmoisture, for 3 hours. Following this reaction period the reactionmixture was cooled to room temperature, then cautiously treated with anexcess of an aqueous ammonium chloride solution, and then extracted withethyl acetate. The resulting extract was washed with water, then driedover anhydrous sodium sulfate and evaporated to dryness.Recrystallization from methylene dichloride/hexane gaveB-homo-l7a-methyl-l9-nor-A androstene 3,8,175- diol.

EXAMPLE IX A solution of 1 gram of B-homo-l9-nor-A-androsten-3fi-ol-l7-one in cc. of anhydrous, thiophene-free benzene wasadded, under an inert nitrogen atmosphere,

to a solution prepared by dissolving 1.4 grams of potassium in 30 cc. oft-amyl alcohol, and a slow current of purified acetylene was then passedthrough the thus-prepared solution for hours. Following this reactionperiod the reaction mixture was diluted with water and then extractedwith benzene. The resulting extract was then washed with water untilneutral, then dried over anhydrous sodium sulfate. Next, evaporation ofthe benzene and chromatography of the residue on alkaline alumina gavein the hexane/benzene (2:3 by volume, respectively) fractions a productwhich, upon recrystallization from acetone/hexane, gave pureB-homo-17aethynyl-19-nor-A -androstene-3,8,l7fl-diol.

EXAMPLE X A solution of 1 gram of B-homo-lh-ethylnyl-l9-nor- A-androstene-3fl,17,8-diol in 40 cc. of pyridine containing 400 mg. ofpre-hydrogenated 2% palladium-oncalcium carbonate hydrogenation catalystwas hydrogenated at room temperature and atmospheric pressure until 1.1molar equivalents of hydrogen had been absorbed. At this point thereaction was stopped and the catalyst was removed by filtration throughCelite, then washed with ethyl acetate. The washings were then added tothe filtrate and the combined solution was evaporated to dryness undervacuum. The resulting residue was dissolved in ethyl acetate, and thethus-obtained solution was washed with dilute hydrochloric acid and thenwith water until neutral, dried over anhydrous sodium sulfate andevaporated to dryness. Recrystallization from acetone gaveB-homo-19-nor-17u-vinyl-A -androstene 35,17 8- diol.

EXAMPLE XI A solution of 8.5 grams of 1-chloro-2-fluoroethylene in cc.of anhydrous diethyl ether was added dropwise, with stirring, at 0 C.over a half hour period, to 15 cc. of a 1.4 N solution of methyl lithiumin anhydrous diethyl ether, maintained under an inert nitrogenatmosphere, and this mixture was then held at room temperature, withstirring, for an additional minutes.

Next, a solution of 0.5 gram of B-homo-l9-nor-A androsten-3Bol-17-one in20 cc. of anhydrous diethyl ether was added dropwise, with stirring,over a 15 minute period, following which the resulting reaction mixturewas held at room temperature, with stirring, for 18 hours. Followingthis reaction period the reaction mixture was poured into ice water andthen extracted with diethyl ether. The ether extract was then washedwith water, dried over anhydrous sodium sulfate and concentrated undervacuum. Chromatography of the residue on basic alumina, using petroleumether/diethyl ether (8:2, respectively, by volume) as th eluant,followed by crystallization from methanol, gaveB-homo-lh-fiuoroethynyl-19-nor-A -androstene-3fl,17fl-diol.

By repeating this procedure in every detail but one, namely, replacing1-chl0ro-2-fluoroethylene with 1,2-dichloroethylene, 1,2-dibromoethyleneand 1-chloro-3,3,3- trifluoropropyl-l-ene, respectively, thecorresponding 17ahaloalkynyl derivatives, namely, B-hOm0-17a-Chl0r0-ethynyl-19-nor-A -androstene 3fi,17[3 diol; B-homo-17ot-bromoethynyl-19-nor-A -androstene 35,175 diol andB-homo-17a-trifluoropropynyl 19 nor-A -androstene-3,8,l7[3-diol,respectively, were obtained.

EXAMPLE XII A mixture of 1 gram of B-homo-19-nor-A-androsten-3B-ol-17-one, 8 cc. of pyridine and 4 cc. of acetic anhydridewas allowed to stand at room temperature overnight. Following thisreaction period the reaction mixture was poured into ic water and theresulting precipitate collected by filtration, washed with water anddried. Crystallization from acetone/hexane gave B-homo- 19-nor-A-androsten-3B-ol-17-one 3-acetate, identical to that prepared asdescribed in Example V hereinabove.

By repeating this procedure in every detail but one,

namely, replacing B-homo-l9-nor-A -androsten-3,B-ol- 17-one with:

respectively, the corresponding 3-acetates (and, in the case ofB-homo-19-nor-A -androstene-3fi,l7fi diol, the corresponding3,17-diacetate) were obtained.

Similarly, by replacing acetic anhydride with propionic anhydride,cyclopentylpropionic anhydride, B-chloropropionic anhydride, butyricanhydride, caproic anhydride and enanthic anhydride, respectively, andusing in turn each of the nine B-homo steroids mentioned above, the

corresponding propionates, cyclopentylpropionates, ,8- 2

chloropropionates, butyrates, caproates and enanthates were obtained.

EXAMPLE XIII A mixture of 1 gram of B-homo-l7a-methyl-l9-nor A-androstene-3;3,17,8-diol, 1 gram of p-toluenesulfonic acid monohydrate,50 cc. of acetic acid and 25 cc. of acetic anhydride was allowed tostand at room temperature for 24 hours. Following this reaction periodthe reaction mixture was poured into water and stirred until the excessacetic anhydride had hydrolyzed. Next, the product was isolated byextraction with methylene dichloride, and the extract was washed withwater until neutral, then dried over anhydrous sodium sulfate andevaporated to dryness. Crystallization of the residue fromacetone/diethyl ether gave B-homo-l7a-methyl-19-nor- A-androstene-3B,l7fi-diol 3,17-diacetate.

This procedure was then repeated in every detail but one, namely, B homo17u-methyl-19-nor-A -androstene-3fl,l7fi-diol was replaced byB-homo-19-nor-17a-vinyl-A -androstene-3;3,l7/i-diolB-homo-l7a-ethynyl-l9-nor-A -androstene-35,l7,8-

diol; B-homo-17a-fluoroethynyl-19-n0r-A -androstene-3/i,

17fl-diol; B'homo,l7a-chloroethynyl-l9-nor-A -androstene3,3,

17fi-di0l; B-homo-l7a-bromoethynyl-19-nor-A -androstene-Bp,

17;3-diol; B-homo-l7a-trifluoropropynyl-19-nor-A -androstene- 3p3,178-diol; B-homo-Not-methyl-19-nor-A -androstene-Sfi-17fi-diol 3-acetate;B-homo-19-nor-17a-vinyl-A -androstene-3p,17p-diol;

3-propionate; B-homol 7a-ethynyl-l 9-nor-A -andrstene-3 fl, 17,8-diol3-cyclopentyl-propionate; B-homo-l7a-fluoroethynyl-19-nor-A-androstene-3/3,

17fi-diol 3-,8-chloropropionate; B-homo-17a-chloroethynyl-19-nor-A-androstene-Bfl,

17/i-diol 3-butyrate; B-homo-l7u-bromoethynyl-19-nor-A -androstene-Iip,

17B-diol 3-caproate, and B-homo-17u-trifluoropropynyl-19-nor-A-androstene- 35,17fl-diol 3-enanthate,

respectively. In each case, the corresponding 3,17-diester,

namely,

B-homo-19-nor-17ot-vinyl-A -androstenefi,17(i-diol 3,17-diacetate;

10 B-homo-l7a-ethynyl-19-nor-A -androstene-3p,17fl-diol 3,17-diacetate;B-homo-lh-fiuoroethynyl-19-nor-A -androstene- 3fi,l7fl-diol3,17-diacetate; B-homo-l7u-chloroethynyl-l9-nor-A -androstene-35,17,8-dio1 3,17-diacetate; B-horno-lh-bromoethynyl-19-nor-A-androstene- 3/i,l7fi-diol 3,17-diacetate;B-homo-l7a-trifluoropropynyl-19-nor-A -androstene- 3 ,8, 17,8-diol3,17-diacetate;

B-homo-l7a-methyl-l9-nor-A -androstene-3B,17B-diol 3,17-diacetate(identical to that prepared as described hereinabove)B-homo-l9-nor-17a-vinyl-A -androstene-iifl,17p-diol 3-propionatel7-acetate;

B-homo-17a-ethynyl-19-nor-A -androstene-3fl,17/3-diol3-cyclopentylpropionate 17-acetate;

B-homo-l7a-fluoroethynyl-19-nor-A -androstene-3fi,

l7p-diol 3-13-chloropropionate 17-acetate;

B-homo-l7a-chloroethynyl-19nor-A androstene-Sfi,

l7fl-diol 3-butyrate 17-acetate;

B-homo-l7a-bromoethynyl-l9-nor-A -androstene-Ilfl,

l7fl-diol 3-caproate 17-acetate, and

B-homo-l7ot-trifluoropropynyl-l9-nor-A -androstene- 33,17fl-diolB-enanthate 17-acetate;

respectively was obtained.

EXAMPLE XIV A solution of 1 gram of B-homo-17u-methyl-19-nor- Aandrostene-3;8,17,8-diol 3,17-diacetate in 50 cc. of methanol wasrefluxed for 3 hours with 500 mg. of potassium hydroxide dissolved in 1cc. of water. Following this reaction period the reaction mixture waspoured into ice water and the thus-formed precipitate collected byfiltration, washed with water until neutral and then dried.Recrystallization from methylene dichloride/diethyl ether gave B homo 17a methyl-l9-nor-A -androstene-3B, 17,8-diol 17-acetate.

By repeating this procedure in every detail but one, namely, replacing Bhomo-l7a-methyl-l9-nor-A -androstene-3;8,17fl-diol 3,17-diacetate with:B-homo-19-nor-17ct-vinyl-A -androstene-3B,17,8-diol 3, 17-diacetate;

B-homo-17a-ethynyl- 19-nor-A -androstene-3 3, 17/3- diol 3,17-diacetate;B-homo-17a-fluoroethynyl-l9-nor-A -androstene-BB,

l7l9-diol 3,17-diacetate; B-homo-l7u-chloroethynyl-19-nor-A-androstene-3fl,

17fl-diol 3,17-diacetate; B-homo-17abromoethynyl-19-nor-A-androstene-BB,

17B-diol 3,17-diacetate, and B-homo-17a-trifluoropropynyl-19-nor-A-androstene- 3fl,17,6-diol 3,17-diacetate, respectively, thecorresponding 17-monoacetates were obtained.

EXAMPLE XV To a solution of 1 gram of B- omo-19-nor-A androsten-33-ol-17-one in 25 cc. of benzene there was added 4 cc. of dihydropyran.Next, approximately 5 cc. of the mixture of benzene and dihydropyran wasdistilled oil? to remove moisture, and the remaining mixture was thencooled to room temperature. To the cooled mixture there was then added0.1 gram of p-toluenesulfonic acid, and the resulting reaction mixturewas held at room temperature for 72 hours. Following this reactionperiod the reaction mixture was washed with an aqueous 5% sodiumcarbonate solution and then with water until neutral, then dried overanhydrous sodium sulfate and evaporated to dryness. The dry residue waschromatographed by passing it, dissolved in hexane, through a column ofneutral alumina, thus giving B-homo-3B-tetrahydropyranyloxy-19- nor-A-androsten-17-one.

This procedure was then repeated in every detail but one, namely,B-homo-l9-nor-A -androsten-311-ol-l7- one was replaced by:

B-horno-l9-n0r-A -androstene-3;8,l7;8-diol; B-homo-17a-methyl-19-nor-A-and rstene-31i, l 713- diol; B-homo-l7u-methyl-19-nor-A-androstene-313,1713-diol 3-acetate; B-homo-l7a-methyl-l9-nor-A-androstene-3fi,1713-diol 17-acetate; B-homo-19-nor-17a-vinyl-M-andr0stene-313,1713-cli01; B-homo-l9-nor-17a-vinyl-A-androstene-313,1713-dio1 3-acetate; B-horno-l9-nor-17a-vinyl-A-androstene-313,l71i-diol 17-acetate; B-homo-l7m-ethynyl-l9-nor-A-androstene-31i,17B-

diol; B-homo-l7ix-ethynyl-19-nor-A -androstene-3B,171idiol B-acetate;B-homo-l7a-ethynyl-l9-nor-A -androstene-3 13,1713- diol 17-acetate;B-homo-l7a-fluoroethynyl-19-nor-A -androstene-3 1i,

l71i-diol; B-homo-17a-fluoroethynyl-19-nor-A -androstene-313,

17,8-di0l 3-acetate; B-horno-17a-fluoroethynyl-19-nor-A -androstene-31i,

171i-diol l7-acetate; B-homo-l7a-chloroethynyl-19-nor-A -andr0stene-313,

1713-di0l; B-homo-17u-ch10r0ethynyl-19nor-A -androstene-313,

1713-dio1 3-acetate; B-homo-l7a-chloroethynyl-l9-nor-A -androstene-313,

l7B-dio1 l7-acetate; B-homo-l7a-bromoethynyl-19-nor-A -androstene-313,

171i-diol; B-homo-17u-bromoethynyl-l9-nor-A -androstene-311,

171i-d10l 3-acetate; B-homo-l7a-bromoethynyl-l9-nor-A -androstene-3 6,

17B-diol l7-acetate; B-homo-17a-trifiuoropropynyl-19-nor-A -androstene-313,1713-diol; B-homo-17a-trifluoropropynyl-l9-n0r-A -androstene-313-1713-diol S-acetate, and

-B-homo-17u-trifiuoropropynyl-19-nor-A -androstene- 318,l7B-diol17-acetate,

respectively; the corresponding tetrahydropyranyl ethers, namely,

B-homo-3 13,171i-bis(tetrahydropyranyloxy)-19-nor- A -androstene;

B-homo-3 13, l 713-bis (tetrahydropyranyloxy) l 7u-methyll9-n0r-A-androstene;

B-homo-l7a-methyl-171i-tetrahydropyranyloxyl9-nor- A -androsten-313-ol3-acetate;

B-homo-318-tetrahydropyranyloxy-17a-methyl-19-nor- A -androsten- 1713-01 l7-acetate;

B-homo-31-i, 1713-bis (tetrahydropyranyloxy 19-nor- 170L- vinyl-A-androstene;

B-homo-l9-nor-1713-tetrahydropyranyloxyl7a-vinyl- A -androsten-313-ol3-acetate;

B-h0mo-31i-tetrahydropyranyloxy- 1 9-norl 7a-vinyl- A -androsten-1 78-01 17-acetate;

B-homo-313,1713-bis(tetrahydropyranyloxy)-l7tx-ethynyl- 19-n0r-A-androstene;

B-homo- 17a-ethynyl-l713-tetrahydropyranyloxy-l9-nor- A-andr0sten-3;8-ol 3-acetate;

B-homo-3 8-tetrahydropyranyloxy-l7u-ethyny1-19-nor- A -androsten-1713-oll7-acetate;

B-homo-31i,171i-bis(tetrahydropyranyloxy) -l7ot-flu0roethynyll 9-nor-A-androstene;

B-homo-17a-fluoroethynyl-171i-tetrahydropyranyloxy- 19-nor-A-androsten-3 13-01 3 -acetate;

B-h omo-313-tetrahydropyranyl0xyl 7a-fiuoroethynyll 9- nor-A-androsten-l713-ol 17-acetate;

B-homo-313,1713-bis(tetrahydropyranyloxy)-17a-chloroethynyll9-n0r-A-androstene;

B-homo-17a-chl0roethynyl-1713-tetrahydropyranyloxyl9-nor-A-androsten-313-ol B-actate;

B-homo-313-tetrahydropyranyloxy-17ot-chloroethynyl-l9- nor-A -androsten-1713-01 l7-acetate;

B-hom0-3 13, 1713-bis (tetrahydropyranyloxy) -17oc-b1OII10- ethynyll9-nor-A -androstene;

B-homo-17u-bromoethynyl-l713-tetrahydropyranyloxyl9-nor-A -androsten-313-01 3 -acetate;

B-h0m0-313-tetrahydropyranyl0xy-17a-bromoethynyl-l9- nor-A -androsten-1713-01 l7-acetate;

B-homo-l 7a-trifiuoropropynyl-1713-tetrahydropyranyloxyl 9-nor-A-androsten-3 13-01 3-acetate, and

B-homo-3 13-tetrahydropyranyloxy-1 7oc-il'ifltl0l0 pro pynyl- 19-nor-A-androsten- 1713-01 l7-acetate,

respectively, were obtained.

Similarly, by replacing dihydropyran with dihydrofuran, thecorresponding tetrahydrofuranyloxy ethers were obtained.

EXAMPLE XVI By treating B-homo-313-tetrahydropyranyloxy-l9-nor- A-androsten-l7-one in the manner described in Example VII hereinabove,B-hom0-313-tetrahydropyranyloxy-19-nor-A -andr0sten-1713-01 wasobtained.

Reaction of this 1713-01 with acetic anhydride in pyridine in the mannerdescribed in Example XII hereinabove gaveB-homo-31i-tetrahydropyranyloxy-19-nor-A -androsten-l713-ol l7-acetate.

A solution of 1 gram of this l7-acetate in cc. of methanol was thenadmixed with 1 gram of oxalic acid in 20 cc. of water, and the resultingreaction mixture was refluxed for 1 hour. Following this reaction periodthe reaction mixture was concentrated to about 20 cc. under vacuum, thenpoured into ice water. The resulting precipitate was collected byfiltration, washed with water until neutral, then dried.Recrystallization of the dry precipitate from acetone/hexane gaveB-homo-l9-nor- A -androstene-313,17fi-diol 17-acetate.

EXAMPLE XVII B-l1om0-l9-nor-A -androsten-313-ol-17-one 3-acetate,obtained as described in Example V hereinabove, was reacted with sodiumborohydride in aqueous tetrahydrofuran in the manner described inExample VII hereinabove to give B-homo-19-nor-A -androstene-3,B,1713-diol 3-acetate.

Reaction of this free 1713-01 with dihydropyran in the manner describedin Example XV hereinabove gave B- horno-l71i-tetrahydropyranyloxy19-nor-A -andr0sten- 3 8-ol-3-acetate.

Hydrolysis of this 3-acetate with aqueous methanolic potassium hydroxidein the manner described in Example VI hereinabove gaveB-homo-l7B-tetrahydropyranyloxy- 19-nor-A -androsten-313-ol.

Oxidation of the 3,8-hydroxyl group in this free 313-01 with chromiumtrioxide in pyridine, in the manner described in Example 11hereinabo-ve, gave B-h0m0-171itetrahydropyranyloxy-19-nor-A-androsten-3-one.

A solution of 1 gram of the thus-obtained 3-one in 10 cc. of methanolwas then admixed with 10 cc. of an aqueous 0.1 N solution of potassiumhydroxide, and the resulting reaction mixture, maintained under an inertnitrogen atmosphere, was refluxed for 1 hour. Following this reactionperiod the reaction mixture was poured into ice water, and the resultingprecipitate collected by filtration, washed with water until neutral andthen dried. Recrystallization from methylene dichloride/diethyl ethergave B-homo-17B-tetrahydropyranyloxy-19-nor-A -androsten-3-one.

A solution of 1 gram of B-homo-l7fi-tetrahydropyranyloxy-19-nor-A-androsten-3-one in 50 cc. of anhydrous tetrahydrofuran was added over a30 minute period to a stirred suspension of 1 gram of lithium aluminumhydride in 50 cc. of anhydrous tetrahydrofuran, and the resultingreaction mixture was then refluxed for 2 hours. Following this reactionperiod the reaction mixture was cooled to room temperature thencautiously treated with cc. of ethyl acetate and 2 cc. of water. Next,solid sodium sulfate was added, and the inorganic material filtered offand washed thoroughly with hot ethyl acetate, with the washings beingadded to the filtrate. The combined organic solution was then evaporatedto dryness. Crystallization of the dry residue from acetone/ hexane gaveB-homo-l7fl-tetrahydropyranyloxy-l9-nor- A -androSten-3fi-0l.

EXAMPLE XIX Esterification of B-homo-17p-tetrahydropyranyloxy-19*nor-M-androsten-BB-ol with acetic anhydride in pyridine in the mannerdescribed in Example XII hcreinabove gave B-homo-l7B-tetrahydropyranyloxy-l9-nor A -androsten- 35-01 3-acetate.

Removal of the tetrahydropyranyl group from this 3- acetate in themanner described in Example XVI hereinabove gave Bhomo-19-nor-A-androstene3fl,17,8-diol 3- acetate.

Oxidation of the 17fl-hydr-oxy1 group in this free 17,8- 01 withchromium trioxide in pyridine, in the manner described in Example IIhereinabove, gave B-homo-19- nor-A -androsten-3fi-ol-17-one 3 acetate.

Hydrolysis of this 3-acetate with aqueous methanolic potassium hydroxidein the manner described in Example VI hereinabove gave B-homo-19-nor-A-androsten-3fi-ol- 17-one.

Hydrolysis of B-homo-l9-nor-A -androstene-3/3,l7fldiol 3-acetate in thesame manner gave B-homo-19-nor- A -androstene-3B,17B-diol.

By reacting B-homo-19-nor-A -androsten-3,B-ol-17-one withmethylmagnesium bromide in the manner described in Example VIIIhereinabove, B-homo-l7umethyl-l9-nor- A -androstene-3 3,17B-diol wasobtained.

Similarly, reaction of the 17-one with acetylene in the presence ofpotassium t-amylate in the manner described in Example IX hereinabovegave B-homo-lh-ethynyl- 19-nor-A -androstene-3B,17fi-diol.

Hydrogenation of the thus-obtained 17a-ethynyl derivative in the mannerdescribed in Example X hereinabove gave B-homo-l9-nor-17a-vinyl A-androstene-3p,17;8-diol.

By reacting l-chloro-Z-fluoroethylene with methyl lithium, and thenadding B-homo-19-nor-A -androsten-3fiol-l7-one, in the manner describedin Example XI hereinabove, B-homo-17a-fluoroethynyl-19-nor-A-androstene- 3 3,17,8-diol was obtained.

Similarly, by carrying out the same reaction using 1,2-dichloroethylene, 'l,2-dibromoethylene and 1-chloro-3,3,3-trifluoropropyl-1-ene, respectively, in place of 1-chloro-2-fluoroethylene, B-homo-l'hx-chloroethynyl-l9-nor-Aandrostene-3[i,17[3-diol; B-homo-l7a-bromoethynyl-l9- nor-A-androstene-3fl,17fi-diol and B-homo-17a-trifluoropropynyl-19-nor-A-androstene-3fi,l7 8-diol, respectively, were obtained.

EXAMPLE XX B-homo-l9-nor-A -androsten-3B-ol-17-0ne was esterified, usingacetic anhydride in pyridine in the manner described in Example XIIhereinabove, to give B-horno- 1'9-nor-A -androsten-36-01-17-one3-acetate, identical to that prepared as described in Example XIXhereinabove.

By carrying out this reaction using: B-homo-l9-nor-nor-A-androstene-3,8,17fi-diol; B-homo-l7a-methyl-19-nor-A-androstene-3fi,17/3-diol; B-homo-l9-n0r-17u-vinyl-A -androstene-3 8,l73-diol; B-homo-17u-ethynyl-19-nor-A -androstene-35,17fi-diol;

1 4 B-homo-17a-fluoroethynyll9-nor-A -androstene-3,6, 17/3- diol;B-homo-l7u-bromoethynyl-l9-nor-A -androstene-3fl,17,8-

diol; B-homol 7a-fluoroethynyll9-nor-A -androstene-3/3,17/3- diol, andB-homo-l7 x-trifluoropropynyl-19nor-A -androstene-3B,

17 fi-diol,

respectively, in place of B-homo-19-r1or-A -androsten-3 3- ol-l7-one,the corresponding 3-acetates (and, in the case of B-homo-19-nor-A-androstene-3B,17,8-dio1, the corresponding 3,17-diacetate) wereobtained.

Similarly, by replacing acetic anhydride with propionic anhydride;cyclopentylpropionic anhydride, fl-chloropropionic anhydride, butyricanhydride, caproic anhydride and enanthic anhydride, and using in turneach of the nine B-homo steroids mentioned above, the correspondingpropionates, cyclopentylpropionates, B-chloropropionates, butyrates,caproates and enanthates were obtained.

EXAMPLE XXI B-homo-lh-methyl l9 nor A androstene-3fi,l75- diol wasesterified, using a mixture of acetic anhydride and acetic acid in thepresence of p-toluenesulfonic acid in the manner described in ExampleXIII hereinabove, to give B-homo-17a-methyl-l9-nor Aandrostene-3fi,l7,8- diol 3,17-diacetate.

By carrying out this reaction using:

B-homo-l9-nor-l7u-vinyl-A -androstene-3,8,17(3-diol;B-homo17wethynyl-l9-nor-A -androstene-3fl,17,8-diol;B-homo-l7u-fluoroethynyl-l9-nor-A -androstene- 35,17/3-diol;B-homo-l7a-chloroethynyl-19-nor-A -a-ndrostene- 3fl,l7fi-diol;B-homo-17u-brornoethynyl-19-norA -androstene- 35,17,8-diol;B-homo-l7a-trifluoropropynyl-19-nor-A -androstene- 35,17fi-diol;B-homo-17u-methyl-19-nor-A -androstene-3/3,17,8-diol 3-acetate;B-homo-l9-nor-17ot-vinyl-A4-androstene-3p,17,8-diol 3-propionate;B-homo-17a-ethynyl-19-nor-A -androstene-3,B,17B-diol3-cyclopentylpropionate; B-homo-17a-fluoroethynyl-19-nor-A -androstene-3,8,l7B-diol 3fl-chloropropionate; B-homo-17ot-ehloroethynyl-l9-nor-A-androstene- 36,17 8-di0l 3-butyrate; B-homo-lh-bromoethynyl-19-nor-A-androstene- 3,6,l7fl-di0l 3-caproate, andB-homo-l7a-trifluoropropynyl-l9-nor-A -androstene- 3 5,17,8-diolBenanthate,

respectively, in place of B-homo-17a-methyl-l9-nor-A androstene-3,8,17,i-dio1, the corresponding 3,17-diesters, namely:

B-homo-19-nor-l7a-vinyl-A -androstene-3,8,l7/3-diol 3,17-diacetate;B-homo-l7a-e1hynyl-l9-nor-A -androstene3fl,l7fi-diol 3,17-diacetate;B-horno-17a-fluoroethynyl-l9-nor-A -androstene-3B,17p?- diol3,17-diacetate; B-homo-l7a-chloroethynyl-l9-nor-A -androstene-3fl,17,B-diol 3,17-diacetate; B-hoino-17a-bromoethynyl-l9-nor-A-androstene- 3,8,17fl-diol 3,17-diacetate;B-homo-l7a-trifiuoropropynyl-l9-nor-A -androstene- 3/3,17;6-diol3,17-diacetate; B-homo-l7a-methyl-l9-n0r-A -androstene-3fl,l7fi-diol3,17-diacetate (identical to that prepared as described hereinabove);B-homo-19-nor-17a-vinyl-A -a-ndrostene-3p,17,8-diol 3-propionate17-acetate;

wherein R is selected from the group consisting of the hydroxyl group,hydrocarbon carboxylic acyloxy groups containing less than 12 carbonatoms, the tetrahydrofuranyloxy group and the tetrahydropyranyloxygroup; R is selected from the group consisting of hydrogen, lower alkylgroups, lower alkenyl groups and lower alkynyl groups; R and R takentogether represent the keto group, and R is selected from the groupconsisting of hydrogen, hydrocarbon carboxylic acyl groups containingless than 12 carbon atoms, the tetrahydrofuranyl group and thetetrahydropyranyl group.

2. B-homo-19-nor-A -androsten-SB-ol-17-one.

4. B homo 17oz methyl 19 nor A500) androstene-3B,17,B-diol.

5. B homo 19 nor 17a vinyl A590) androstene-3fl,17;3-diol.

6. B homo 17a ethynyl 19 nor A androstone-3,8,17/3-diol.

7. B homo 170: fluoroethynyl 19 nor A androstene-35,17/8-diol.

8. B homo 17o: chloroethynyl 19 nor A androstene-3/3,17fl-diol.

9. B homo 17a bromoethynyl 19 nor A androstene-3fl,17p-dio1.

10. B homo 17a trifluoropropynyl 19 nor A androstene-3fi, 17/3-diol.

11. A compound represented by the general formula:

wherein R is selected from the group consisting of the hydroxyl group,hydrocarbon carboxylic acyloxy groups containing less than 12 carbonatoms, the tetrahydrofuranyloXy group and the tetrahydropyranyloxygroup; R is selected from the group consisting of hydrogen, lower alkylgroup, lower alkenyl groups and lower alkynyl groups; R and R takentogether represent the keto group, and R is selected from the groupconsisting of hydrogen, hydrocarbon carboxylic acyl groups containingless than 12 carbon atoms, the tetrahydrofuranyl group and thetetrahydropyranyl group.

12. B-homo-19-nor-A -androsten-Bfl-ol-17-one.

13. B-homo-19-nor-A -androstene-3fl,17,8-diol.

14. B homo 17a methyl 19 nor A androstene- 3,8,17/3-di0l.

15. B homo 19 nor 17a vinyl A androstene- 35,17,8-dio1.

16. B homo 17a ethynyl 19 nor A androstene- 3,8,17fl-di0l.

17. B homo a fiuoroethynyl 19 nor A androstene-3;3,17fl-diol.

18. B homo 17a chloroethynyl 19 nor A androstene-3fl,17;8-diol.

19. B homo 17a bromoethynyl 19 nor A an drostene-3,8, 17,6-dio1.

20. B homo 17a trifluoropropynyl 19 nor A androstene-3fl,17;8-diol.

References Cited UNITED STATES PATENTS 3,291,836 12/1966 Tadanier et al.26O---586 3,234,269 2/1966 ileger et al. 260-586 3,059,019 10/1962Ringold 260-586 LEON ZITVER, Primary Examiner.

M. JACOB, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,410,907 November 12, 1968 John A. Edwards It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 2, formulas I, II and III should appear as shown below: O o 0 O(II) l l' 'l o 0 (III) Column 3, line 61, "l-position" should read17-position Column 4, formula X should appear as shown below:

Column 6, line 15, "XVI" should read XIV Column 8, line 16, "ethylnyl"should read ethynyl Column 13, line 50,

"vinyl A should read vinyl-A line 72, "nor-nor" should read nor Column14, line 3, "bromoethynyl" should read chl-oroethynyl line 5,"fluoroethynyl" should read bromoethynyl line 42, "A4" should read ASigned and sealed this 10th day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E., SCHUYLER, JRQ Attesting OfficerCommissioner of Patents

